SUMMARY/ABSTRACT Francisella tularensis is an extremely virulent Gram negative bacterial pathogen capable of causing rapidly progressing lethal infections in literally hundreds of diverse animal species, including humans. Transmission from infected animals to humans occurs via multiple routes including direct contact, arthropod vectors, ingestion and inhalation. The lowest infective dose, fastest disease progression, and highest mortality rates are associated with inhalation acquired infections. F. tularensis invades (or enters) and replicates within many different host cell types, including macrophages, dendritic cells, neutrophils and at least some epithelial cell types. Following entry the bacteria escape the phagosome and replicate within the cytoplasm of the host cell. We have identified a cytoplasmic membrane protein, RipA, that is conserved among pathogenic Francisella species. Mutants lacking RipA escape the phagosome, but fail to replicate once in the cytoplasm. Gene expression patterns in DripA mutants differ from wild type organisms. Herein we present data demonstrating that the RipA protein associates with a transcriptional regulator, IclR, and IclR regulates a restricted number of genes, most notably an operon containing a response regulator, pmrA, that is required for F. tularensis intracellular growth and pathogenesis. Three aims are proposed to characterize RipA and discern its function in host cell adaptation, to determine the role of IclR in modulating the expression of virulence associated genes, and to examine the contribution of three RipA - associated genes to F. tularensis virulence and pathogenesis.